Routine testing for mismatch repair deficiency in sporadic colorectal cancer is justified

This study prospectively examines the accuracy of immunohistochemical staining in the identification of mismatch repair defective (MMRD) colorectal cancer in routine clinical practice. The potential impact of this information on decisions regarding adjuvant treatment and germline testing were quantified. A consecutive series of fresh tissue (836 cancers) was obtained from 786 individuals undergoing curative surgery for colorectal cancer at one institution. As part of normal practice, each tumour was screened for the expression of MLH1 and MSH2 by immunohistochemical staining (IHC) and relevant clinicopathological details were documented. Microsatellite instability (MSI) was assessed using standard markers. Overall, 108 (13%) tumours showed loss of staining for either MLH1 (92 tumours) or MSH2 (16 tumours). The positive predictive value of mismatch repair IHC when used alone in the detection of MSI tumours was 88%, and the negative predictive value was 97%. Specificity and positive predictive value were improved by correlation with microsatellite status. Tumour stage (HR 3.5, 95% CI 2.0-6.0), vascular space invasion (HR 1.9, 95% CI 1.2-3.0) and mismatch repair deficiency (HR 0.2, 95% CI 0.05-0.87) were independent prognostic factors in stages II and III disease. Screening by mismatch repair IHC could reasonably have been expected to prevent ineffective treatment in 3.6% of stage II and 7.6% of stage III patients. The frequency of germline mismatch repair mutations was 0.8%, representing six unsuspected hereditary non-polyposis colorectal cancer (HNPCC) cases. Routine screening of colorectal cancers by mismatch repair IHC identifies individuals at low risk of relapse, and can prevent unnecessary adjuvant treatments in a significant number of individuals. Abnormal immunohistochemistry should be confirmed by microsatellite testing to ensure that false-positive results do not adversely impact on treatment decisions.     

Investigation of pathology,expression and proteomic profiles in human TREM2 variant postmortem brains with and without Alzheimer’s disease

Triggering receptor expressed on myeloid cells 2 TREM2 was identified as a risk factor for late onset Alzheimer’s disease (AD). Here we compared TREM2 cases with a variant (TREM2⁺) and cases without a TREM2 variant (TREM2⁻), considering pathological burden, inflammatory response and altered canonical pathways and biochemical functions between the cohorts. We hypothesised that TREM2⁺ cases would have a loss of function, indicating an altered inflammatory profile compared to TREM2⁻ cases. Immunohistochemistry was performed using antibodies against Aβ, tau and microglia markers in TREM2⁺ cases, with and without AD, which were compared to sporadic TREM2⁻ AD, familial AD and neurologically normal control cases. Aβ and tau load were measured along with the composition of Aβ plaques, in addition to microglial load and circularity. Expression and proteomic profiles were determined from the frontal cortex of selected cases. TREM2⁺ control cases had no Aβ or tau deposition. No differences in the amount of Aβ or tau, or the composition of Aβ plaques were observed between TREM2⁺ and TREM2⁻ SAD cases. There were no differences in microglial load observed between disease groups. However, the TREM2⁺ SAD cases showed more amoeboid microglia than the TREM2⁻ SAD cases, although no differences in the spatial relationship of microglia and Aβ plaques were identified. Visualisation of the canonical pathways and biological functions showed differences between the disease groups and the normal controls, clearly showing a number of pathways upregulated in TREM2⁺ SAD, TREM2⁻ SAD and FAD groups whilst, the TREM2⁺ controls cases showed a downregulation of the majority of the represented pathways. These findings suggest that the TREM2⁺ control group, although carrying the TREM2⁺ variant, have no pathological hallmarks of AD, have altered microglial and expression profiles compared to the TREM2⁺ SAD cases. This indicates that other unknown factors may initiate the onset of AD, with TREM2 influencing the microglial involvement in disease pathogenesis.     

局灶节段透明变性及硬化在判断IgA肾病预后中的意义

目的　探讨IgA肾病 (IgAN)进展为慢性肾功能不全 (CRI)的病理学危险因素。方法　对 6 40例经肾活检确诊的IgAN病人进行平均 5 3个月的追踪观察。用病例对照法研究所有病人的病理学资料 ,同时还对其中 2 0 4例活检当时肾功能正常 ,5年后发展为CRI或终末期肾功能衰竭(ESRF) (n =18)以及 5年后肾功能仍保持正常 (n =186 )的病例进行了比较。结果　弥漫性系膜增生型 (DMP)为最常见的病理型 ,占 5 0 %。 / 间质纤维化 ,>40 %硬化肾小球 , / 血管病变 ,局灶节段透明变性及硬化 (FSHS)的均为预测肾功能恶化的危险因素 ,其中FSHS的意义更大 (P <0 0 0 0 1)。结论　FSHS的存在是IgAN病人正常肾功能进展恶化的显著指标。     

A novel treatment of childhood lymphoblastic non-Hodgkin's lymphoma: early and intermittent use of teniposide plus cytarabine

We treated 24 children and adolescents with stage III or IV lymphoblastic non-Hodgkin's lymphoma, using a protocol designed for patients with poor-prognosis acute lymphoblastic leukemia (ALL). Early therapy consisted of teniposide plus cytarabine administered before and immediately after prednisone, vincristine, and asparaginase. The two- drug combination was also given intermittently with continuous 6- mercaptopurine and methotrexate during the first year of continuation chemotherapy. Periodic intrathecal methotrexate and delayed cranial irradiation were used to prevent central nervous system involvement. Anthracycline compounds, alkylating agents, high-dose methotrexate, and involved-field irradiation were not used in any phase of treatment. Twenty-two (96%) of the 23 evaluable patients achieved complete remission. With a median follow-up of 2 1/2 years, only four patients have relapsed; the remainder have been disease-free for eight months to more than five years. The projected four-year continuous complete remission rate is 73% for all patients and 79% for the 19 with mediastinal involvement at diagnosis. These results demonstrate that use of teniposide plus cytarabine with an otherwise conventional plan of ALL therapy is an effective approach to the treatment of childhood lymphoblastic lymphoma.     

Occurrence of the common acute lymphoblastic leukemia antigen on blast cells of a patient with chronic myelomonocytic leukemia in non-lymphoid blastic phase

Leukemias showing a conspicuous lymphoid phenotype, ie, those that are HLA-DR positive, common acute lymphoblastic antigen (cALLA) positive, terminal deoxynucleotidyl transferase (TdT) negative, as well as myeloperoxidase positive (MPO), could be considered so-called mixed leukemias. Leukemias with biphenotypic blasts have to be distinguished from cases comprising two separate subpopulations that express different lineage-associated characteristics. By use of a simple new method (Immunogold Staining) we examined a case of chronic myelomonocytic leukemia in blastic phase and demonstrated simultaneous staining for MPO/alpha-naphthyl-esterase and expression of the HLA-DR- positive, cALLA-positive, and TdT-negative phenotype. The cALL antigen was detected only on mono- and myelo-monoblasts; its expression was inversely related to the MPO positivity, and it disappeared together with these types of blasts after chemotherapy. On the basis of our findings it remains obscure whether the cALL antigen at the initial presentation was due to the immature monocytic features of the leukemic cells or disclosed on additional lymphoid differentiation pattern of the blasts.